Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture

Invest New Drugs. 2021 Jun;39(3):658-669. doi: 10.1007/s10637-020-01046-6. Epub 2020 Dec 11.

Abstract

Background Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA's influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 μM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.

Keywords: 3D; MCF-7; MCF10A; Radiation; Simvastatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / cytology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / radiotherapy*
  • Cell Culture Techniques
  • Cell Line
  • Cell Physiological Phenomena / drug effects
  • Cell Physiological Phenomena / radiation effects
  • Connective Tissue Growth Factor / metabolism
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Female
  • Histones / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Radiation-Sensitizing Agents / pharmacology*
  • Simvastatin / pharmacology*
  • Survivin / metabolism

Substances

  • BIRC5 protein, human
  • CCN2 protein, human
  • H2AX protein, human
  • Histones
  • Radiation-Sensitizing Agents
  • Survivin
  • Connective Tissue Growth Factor
  • Simvastatin
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 3